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1 system i Valproic Acid en i Valproic Acid 1P35 F5-O207-2/R3 B1P350 Read Highlighted Changes Revised August, 2009 Customer Service: Contact your local representative or find country specific contact information on Package insert instructions must be carefully followed. Reliability of assay results cannot be guaranteed if there are any deviations from the instructions in this package insert. Key to symbols used List Number In Vitro Diagnostic Medical Device Lot Number Expiration Date Store at 2-8 C Consult instructions for use Authorized Representative Serial Number Control Number Reagent Lot Assay CD-ROM Reaction Vessels Sample Cups Septum Manufacturer Replacement Caps See REAGENTS section for a full explanation of symbols used in reagent component naming. 1 1P _Eng_ReIn.indd 1 Colors: Editor: DTP: Black Oneida Ania 9/3/2009 1:53:47 PM

2 NAME ARCHITECT i Valproic Acid INTENDED USE The ARCHITECT i Valproic Acid assay is an in vitro chemiluminescent microparticle immunoassay (CMIA) for the quantitative measurement of valproic acid, an anticonvulsant drug, in human serum or plasma on the ARCHITECT i System with STAT protocol capability. The measurements obtained are used in monitoring levels of valproic acid to help ensure appropriate therapy. SUMMARY AND EXPLANATION OF TEST Valproic acid is a broad-spectrum anticonvulsant drug used solely or in combination with other anticonvulsant drugs for the treatment of absence seizures. 1,2 It also has demonstrated effectiveness in the management of generalized tonic-clonic and myoclonic seizures, as well as atypical absence, simple and complex partial and mixed grand mal and petit mal seizures. 1,3,4 The capability of treating many types of seizures with a single anticonvulsant has resulted in the wide-spread use of valproic acid, particularly in children in whom tonic-clonic and myoclonic seizures are most prevalent. 5-7 Valproic acid has proven effective in the treatment of many patients otherwise refractory to other anticonvulsant treatments. Most patients receiving valproic acid do not develop a tolerance to its anticonvulsant effects. 8 BIOLOGICAL PRINCIPLES OF THE PROCEDURE The ARCHITECT i Valproic Acid assay is a one-step STAT immunoassay for the quantitative measurement of valproic acid in human serum or plasma using CMIA technology with flexible assay protocols, referred to as Chemiflex. Sample, anti-valproic acid coated paramagnetic microparticles, and valproic acid acridinium-labeled conjugate are combined to create a reaction mixture. The anti-valproic acid coated microparticles bind to valproic acid present in the sample and to the valproic acid acridinium-labeled conjugate. After washing, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs). An indirect relationship exists between the amount of valproic acid in the sample and the RLUs detected by the ARCHITECT i System optics. For additional information on system and assay technology, refer to the ARCHITECT System Operations Manual, Section 3. REAGENTS Reagent Kit, 100 Tests ARCHITECT i Valproic Acid Reagent Kit (1P35) 1 Bottle (6.6 ml) Anti-valproic acid (mouse, monoclonal) coated goat anti-mouse (GAM) microparticles in TRIS buffer with protein (bovine) stabilizer. Preservative: ProClin Bottle (5.9 ml) Valproic acid acridinium-labeled conjugate in MES buffer with surfactant. Minimum concentration: 40.0 ng/ml. Preservative: ProClin 300. Other Reagents ARCHITECT i Pre-Trigger Solution Pre-Trigger Solution containing 1.32% (w/v) hydrogen peroxide. ARCHITECT i Trigger Solution Trigger Solution containing 0.35 N sodium hydroxide. ARCHITECT i Wash Buffer Wash Buffer containing phosphate buffered saline solution. Preservative: antimicrobial agent. WARNINGS AND PRECAUTIONS For In Vitro Diagnostic Use. Package insert instructions must be carefully followed. Reliability of assay results cannot be guaranteed if there are any deviations from the instructions in this package insert. Safety Precautions CAUTION: This product requires the handling of human specimens. It is recommended that all human sourced materials be considered potentially infectious and be handled in accordance with the OSHA Standard on Bloodborne Pathogens. 9 Biosafety Level 2 10 or other appropriate biosafety practices 11,12 should be used for materials that contain or are suspected of containing infectious agents. Both components contain methylisothiazolones, which are components of ProClin, and are classified per applicable European Community (EC) Directives as: Irritant (Xi). The following are the appropriate Risk (R) and Safety (S) phrases: R43 May cause sensitization by skin contact. S24 Avoid contact with skin. S35 This material and its container must be disposed of in a safe way. S37 Wear suitable gloves. S46 If swallowed, seek medical advice immediately and show this container or label. The microparticles contain sodium azide. Contact with acids liberates very toxic gas. This material and its container must be disposed of in a safe way. For information on the safe disposal of sodium azide and a detailed discussion of safety precautions during system operation, refer to the ARCHITECT System Operations Manual, Section 8. Handling Precautions Do not use reagent kits beyond the expiration date. Do not pool reagents within a kit or between reagent kits. Before loading the ARCHITECT i Valproic Acid Reagent Kit on the system for the first time, the microparticle bottle requires mixing to resuspend microparticles that have settled during shipment. For microparticle mixing instructions, refer to the PROCEDURE, Assay Procedure section of this package insert. Septums MUST be used to prevent reagent evaporation and contamination and to ensure reagent integrity. Reliability of assay results cannot be guaranteed if septums are not used according to the instructions in this package insert. To avoid contamination, wear clean gloves when placing a septum on an uncapped reagent bottle. Once a septum has been placed on an open reagent bottle, do not invert the bottle as this will result in reagent leakage and may compromise assay results. Over time, residual liquids may dry on the septum surface. These are typically dried salts, which have no effect on assay efficacy. For a detailed discussion of handling precautions during system operation, refer to the ARCHITECT System Operations Manual, Section 7. Storage Instructions Do not freeze ARCHITECT i Valproic Acid reagents. The ARCHITECT i Valproic Acid Reagent Kit must be stored at 2-8 C in an upright position and may be used immediately after removal from 2-8 C storage. When stored and handled as directed, reagents are stable until the expiration date. The ARCHITECT i Valproic Acid Reagent Kit may be stored on board the ARCHITECT i System with STAT protocol capability for a maximum of 30 days. After 30 days, the reagent kit must be discarded. For information on tracking onboard time, refer to the ARCHITECT System Reagents may be stored on or off the ARCHITECT i System. If reagents are removed from the system, store them at 2-8 C (with septums and replacement caps) in an upright position. For reagents stored off the system, it is recommended that they be stored in their original trays and boxes to ensure they remain upright. If the microparticle bottle does not remain upright (with a septum installed) while in refrigerated storage off the system, the reagent kit must be discarded. For information on unloading reagents, refer to the ARCHITECT System Indications of Reagent Deterioration When a control value is out of the specified range, it may indicate deterioration of the reagents or errors in technique. Associated test results are invalid and samples must be retested. Assay recalibration may be necessary. For troubleshooting information, refer to the ARCHITECT System Operations Manual, Section P _Eng_ReIn.indd 2

3 INSTRUMENT PROCEDURE The ARCHITECT i Valproic Acid assay file must be installed on the ARCHITECT i System with STAT protocol capability from an ARCHITECT assay CD-ROM before performing the assay (refer to the PROCEDURE, Materials Required but not Provided section). For detailed information on assay file installation and on viewing and editing assay parameters, refer to the ARCHITECT System Operations Manual, Section 2. For information on printing assay parameters, refer to the ARCHITECT System For a detailed description of system procedures, refer to the ARCHITECT System Operations Manual. The default result unit for the ARCHITECT i Valproic Acid assay is µg/ml. Alternate result units, µmol/l or mg/l, may be selected for reporting results by editing assay parameter Result concentration units to µmol/l or mg/l. The conversion formulas used by the system are as follows: Conversion Formula: ( in µg/ml) x (6.93) = µmol/l Conversion Formula: ( in µg/ml) x (1.00) = mg/l SPECIMEN COLLECTION AND PREPARATION FOR ANALYSIS Specimen Types The specimen collection tubes listed below were verified to be used with the ARCHITECT i Valproic Acid assay. Other specimen collection tubes, including gel separation tubes, have not been tested with this assay. Human serum Human plasma collected in: lithium heparin sodium heparin potassium EDTA sodium EDTA Plasma samples from different anticoagulant tube types should not be used interchangeably for monitoring valproic acid. Liquid anticoagulants may have a dilution effect resulting in lower concentrations for individual patient specimens. The ARCHITECT i System does not provide the capability to verify specimen type. It is the responsibility of the operator to verify that the correct specimen types are used in the ARCHITECT i Valproic Acid assay. Specimen Conditions Do not use specimens with the following conditions: heat-inactivated specimens grossly hemolyzed (>500 mg/dl) obvious microbial contamination cadaver specimens or any other body fluids For accurate results, serum and plasma specimens should be free of fibrin, red blood cells, and other particulate matter. Serum specimens from patients receiving anticoagulant or thrombolytic therapy may contain fibrin due to incomplete clot formation. Use caution when handling patient specimens to prevent cross contamination. Use of disposable pipettes or pipette tips is recommended. For optimal results, inspect all specimens for bubbles. Remove bubbles with an applicator stick before analysis. Use a new applicator stick for each specimen to prevent cross contamination. Preparation for Analysis Follow the tube manufacturer s processing instructions for serum and plasma collection tubes. Gravity separation is not sufficient for specimen preparation. Mix thawed specimens thoroughly by low speed vortexing or by inverting 10 times. Visually inspect the specimens. If layering or stratification is observed, continue mixing until specimens are visibly homogeneous. To ensure consistency in results, specimens must be transferred to a centrifuge tube and centrifuged before testing if they contain fibrin, red blood cells, or other particulate matter, they require repeat testing, or they were frozen and thawed. Transfer clarified specimen to a sample cup or secondary tube for testing. Centrifuged specimens with a lipid layer on the top must be transferred to a sample cup or secondary tube. Care must be taken to transfer only the clarified specimen without the lipemic material. Storage Specimens may be stored on or off the clot or red blood cells for up to two days at room temperature. 13 Specimens removed from the clot or red blood cells may be stored up to seven days refrigerated at 2-8 C. 13 Serum or plasma specimens can be stored up to three months at -20 C or colder. 13 Avoid more than five freeze/thaw cycles. Shipping Before shipping specimens, it is recommended that specimens be removed from the clot or red blood cells. When shipped, specimens must be packaged and labeled in compliance with applicable state, federal and international regulations covering the transport of clinical specimens and infectious substances. Specimens may be shipped ambient or on wet or dry ice. Do not exceed the storage limitations listed above. PROCEDURE Materials Provided 1P35 ARCHITECT i Valproic Acid Reagent Kit Materials Required but not Provided System with STAT protocol capability 8K30 ARCHITECT i System - WW (excluding US) - Addition C, version 7.0 or higher (for use with ARCHITECT i2000 or i2000 SR Systems) 6L81 ARCHITECT i System - US - Addition C, version 7.0 or higher (for use with ARCHITECT i2000 or i2000 SR Systems) 1P60 ARCHITECT i1000 SR System - US Special Edition, version 6.0 or higher 1P61 ARCHITECT i1000 SR System - WW (excluding US) Special Edition, version 4.0 or higher 1P35-01 ARCHITECT i Valproic Acid Calibrators 6E20-10 Abbott Immunoassay-MCC (Liquid) or other commercial controls Pipettes or pipette tips (optional). For information on materials required for maintenance procedures, refer to the ARCHITECT System Operations Manual, Section 9. Assay Procedure Before loading the ARCHITECT i Valproic Acid Reagent Kit on the system for the first time, the microparticle bottle requires mixing to resuspend microparticles that have settled during shipment. After the first time the microparticles have been loaded, no further mixing is required. Invert the microparticle bottle 30 times. Visually inspect the bottle to ensure microparticles are resuspended. If microparticles remain adhered to the bottle, continue to invert the bottle until the microparticles have been completely resuspended. If the microparticles do not resuspend, DO NOT USE. Contact your local Abbott representative. Once the microparticles have been resuspended, place a septum on the bottle. For instructions on placing septums on bottles refer to the Handling Precautions section of this package insert. Load the ARCHITECT i Valproic Acid Reagent Kit on the ARCHITECT i System with STAT protocol capability. Verify that all necessary assay reagents are present. Ensure that septums are present on all reagent bottles. Order calibration, if necessary. For information on ordering calibrations, refer to the ARCHITECT System Operations Manual, Section 6. Order tests. For information on ordering patient specimens and controls and for general operating procedures, refer to the ARCHITECT System 3 1P _Eng_ReIn.indd 3

4 The minimum sample volume is calculated by the system and is printed on the Orderlist report. No more than 10 replicates may be sampled from the same sample cup. To minimize the effects of evaporation, verify adequate sample cup volume is present prior to running the test. Priority: 70 µl for the first ARCHITECT i Valproic Acid test plus 20 µl for each additional ARCHITECT i Valproic Acid test from the same sample cup. 3 hours on board: 150 µl for the first ARCHITECT i Valproic Acid test plus 20 µl for each additional ARCHITECT i Valproic Acid test from the same sample cup. If using primary or aliquot tubes, use the sample gauge to ensure sufficient patient specimen is present. Prepare calibrators and controls. Valproic Acid Calibrators and controls should be prepared according to their respective package inserts. To obtain the recommended volume requirements for the ARCHITECT i Valproic Acid Calibrators, hold the bottles vertically and dispense 5 drops of each calibrator into each respective sample cup. Dispense 150 µl of each control into each respective sample cup. Load samples. For information on loading samples, refer to the ARCHITECT System Press RUN. For additional information on principles of operation, refer to the ARCHITECT Operations Manual, Section 3. For optimal performance, it is important to follow the routine maintenance procedures defined in the ARCHITECT System Operations Manual, Section 9. If your laboratory requires more frequent maintenance, follow those procedures. Specimen Dilution Procedures Specimens with a valproic acid value exceeding µg/ml are flagged with the code > and may be diluted with the Manual Dilution Procedure. Manual dilutions should be performed as follows: The suggested dilution for a valproic acid test is 1:10. Add 10 µl of the patient specimen to 90 µl of ARCHITECT i Valproic Acid Calibrator A. The operator must enter the dilution factor in the Patient or Control order screen. The system will use this dilution factor to automatically calculate the concentration of the sample before dilution. For detailed information on ordering dilutions, refer to the ARCHITECT System Calibration To perform an ARCHITECT i Valproic Acid calibration, test calibrators A, B, C, D, E, and F in duplicate. A single sample of each valproic acid control level must be tested to evaluate the assay calibration. Ensure that assay control values are within established ranges. Calibrators should be priority loaded. Calibration Range: µg/ml. Once an ARCHITECT i Valproic Acid calibration is accepted and stored, all subsequent samples may be tested without further calibration unless: A reagent kit with a new lot number is used. Controls are out of range. For detailed information on how to perform an assay calibration, refer to the ARCHITECT System Operations Manual, Section 6. QUALITY CONTROL PROCEDURES The recommended control requirement for the ARCHITECT i Valproic Acid assay is that a single sample of each control level be tested once every 24 hours each day of use. If the quality control procedures in your laboratory require more frequent use of controls to verify test results, follow your laboratory-specific procedures. Each laboratory should establish control ranges to monitor the acceptable performance of the assay. If a control is out of its specified range, the associated test results are invalid and must be retested. Recalibration may be indicated. Verification of Assay Claims For protocols to verify package insert claims, refer to the ARCHITECT System Operations Manual, Appendix B. The ARCHITECT i Valproic Acid assay belongs to method group 2. Use ARCHITECT i Valproic Acid Calibrators in place of MasterCheck as described in the ARCHITECT System Operations Manual, Appendix B. RESULTS Calculation The ARCHITECT i Valproic Acid assay uses a 4 Parameter Logistic Curve Fit (4PLC, Y-weighted) data reduction method to generate a calibration curve. Flags Some results may contain information in the Flags field. For a description of the flags that may appear in this field, refer to the ARCHITECT System Measurement Range (Reportable Range) The measurement range of the ARCHITECT i Valproic Acid assay, verified by linearity studies, is 2.00 µg/ml to µg/ml. LIMITATIONS OF THE PROCEDURE If the ARCHITECT i Valproic Acid assay results are inconsistent with clinical evidence, additional testing is suggested to confirm the result. For diagnostic purposes, results should be used in conjunction with other data; e.g., symptoms, results of other tests, clinical impressions, etc. Plasma samples from different anticoagulant tube types should not be used interchangeably for monitoring valproic acid. Use of citrate should be performed only when the blood is collected in a full tube so as not to incur a dilution effect. Specimens from patients who have received preparations of mouse monoclonal antibodies for diagnosis or therapy may contain human anti-mouse antibodies (HAMA). 14,15 Such specimens may show either falsely elevated or depressed values when tested with assay kits that employ mouse monoclonal antibodies. 15 Heterophilic antibodies in human serum can react with reagent immunoglobulins, interfering with in vitro immunoassays. 16 The presence of heterophilic antibodies in a patient specimen may cause anomalous values to be observed. Additional information may be required for diagnosis. EXPECTED VALUES There is no precise relationship between serum valproic acid levels and control of seizures, 17 although most patients require at least a serum level of 50 µg/ml for effective therapy. 3,4 A therapeutic range of 50 to 100 µg/ml has been suggested for valproic acid. 1-3 Due to great individual differences in dosage requirements to achieve efficacious therapy, determination of valproic acid serum concentrations is required to direct effective therapy. 3,7,18 Refer to the drug manufacturer s package insert or the Physicians Desk Reference (PDR) for proper drug dosage and for valproic acid measurement sampling times. The main side effects of valproic acid are gastrointestinal. Nausea, vomiting, diarrhea, etc. have been reported in up to 16% of adults and over 22% of children receiving valproic acid. 19 CNS disturbances are usually transient and may be eliminated by reducing the dosage of any concomitantly administered anticonvulsant. 19 A rare adverse side effect of valproic acid is hepatic dysfunction. 4 SPECIFIC PERFORMANCE CHARACTERISTICS Performance was evaluated on the ARCHITECT i2000 SR System. Precision The ARCHITECT i Valproic Acid assay is designed to have an assay precision of 7% total CV for concentrations from 20 to 150 µg/ml. A study was performed with guidance from the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) Protocol EP5-A2. 20 Abbott Immunoassay-MCC (Liquid) (Levels 1, 2, and 3) and four human serum panels were assayed using three lots of reagents in replicates of two at two separate times per day for 20 days on three instruments. Each reagent lot used a single calibration curve throughout the study. Data from this study are summarized in the following tables.* Instru- Reagent Mean Within Run Total Sample ment Lot n (µg/ml) SD %CV SD %CV Level Level P _Eng_ReIn.indd 4

5 Instru- Reagent Mean Within Run Total Sample ment Lot n (µg/ml) SD %CV SD %CV Level Panel Panel Panel Panel Recovery The ARCHITECT i Valproic Acid assay is designed to have a mean recovery of 100 ± 10%. A study was performed on five serum samples and five plasma samples, where valproic acid was spiked into the samples to target concentrations of 0, 15, 30, 75, and 113 μg/ml. The concentration of valproic acid was determined using the ARCHITECT i Valproic Acid assay and the resulting percent recovery was calculated. The mean percent recovery at each target concentration of the ARCHITECT i Valproic Acid for serum ranged from 92% to 98% and for plasma ranged from 91% to 99%.* Linearity The ARCHITECT i Valproic Acid assay is designed to have a mean recovery of 100 ± 10% of the expected results for the diluted samples. A linearity study was performed by diluting five serum samples and five plasma samples with the ARCHITECT i Valproic Acid Calibrator A. The concentration of valproic acid was determined using the ARCHITECT i Valproic Acid assay and the resulting percent recovery was calculated. The individual percent recovery of the ARCHITECT i Valproic Acid for serum ranged from 83% to 118% and for plasma ranged from 96% to 111%.* The mean percent recovery of the ARCHITECT i Valproic Acid assay for serum ranged from 94% to 105% and for plasma ranged from 98% to 103%.* Representative data from this study is summarized in the following tables.* ARCHITECT i Valproic Acid Serum Samples Observed Specimen Dilution Factor (µg/ml) % Recovery a 1 Undiluted : : : Undiluted : : : Undiluted : : : ARCHITECT i Valproic Acid Plasma Samples Observed Specimen Dilution Factor (µg/ml) % Recovery a 1 Undiluted : : ARCHITECT i Valproic Acid Plasma Samples Observed Specimen Dilution Factor (µg/ml) % Recovery a 1: Undiluted : : : Undiluted : : : a % Recovery = Observed Diluted (µg/ml) x Dilution Factor Observed Undiluted (µg/ml) x 100 Sensitivity Analytical Sensitivity Analytical sensitivity is defined as the lower limit of detection and is estimated as the mean of the blank sample plus two times the SD obtained on the blank sample. The ARCHITECT i Valproic Acid assay is designed to have a sensitivity of 2.00 µg/ml. Limit of Blank (LoB) and Limit of Detection (LoD) The LoB and LoD of the ARCHITECT i Valproic Acid assay were determined with guidance from CLSI Protocol EP17-A 21 using proportions of false positives (α) less than 5% and false negatives (β) less than 5%. These determinations were performed using one blank (60 replicates) and five low level valproic acid samples (15 replicates each); LoB = 0.27 µg/ml and LoD = 0.51 µg/ml.* Specificity The specificity of the ARCHITECT i Valproic Acid assay was determined by studying the cross-reactivity of compounds whose chemical structure or concurrent usage could cause potential interference with the ARCHITECT i Valproic Acid assay. Specificity of the assay was determined in the absence and presence of valproic acid by spiking each compound into human serum specimens with valproic acid levels targeted to 50 and 100 µg/ml. The samples were assayed and the valproic acid concentrations of the spiked samples were compared to the control serum. The data are summarized in the following tables.* Compound Name µg/ml Valproic Acid (µg/ml) % Cross- Reactivity b % Cross- Reactivity b 3-keto-valproic acid hydroxy-valproic acid hydroxy-valproic acid ene-valproic acid (2-N-propyl-4-pentenoic acid) 2-propyl-glutarate hydroxy-valproic acid Propyl glutaric acid n-Propyl-3-hydroxy pentanoic acid (Rac-erythreo-3-hydroxy valproic acid) 2-n-Propyl-5-hydroxy pentanoic acid 2-Propyl-4-pentenoic acid Propyl-2-pentenoic acid a Difference = Measured value of sample spiked with Cross-Reactant Measured value of control (Measured value with Cross-Reactant) b (Measure value of Control) % Cross-Reactivity = 100 x Amount of Cross-Reactant Added 5 1P _Eng_ReIn.indd 5

6 Therapeutic Drug Name µg/ml Valproic Acid (µg/ml) % Recovery b % Recovery b Clonazepam Acetyl Cysteine Ampicillin-Na Ascorbic acid Cyclosporine Cefoxitin-Na Heparin Levodopa Methyldopa +1, Metronidazole Phenylbutazone Doxycycline HCl Acetylsalicylic Acid Rifampicin Acetaminophen Ibuprofen Theophylline a Difference = Measured value of sample spiked with Cross-Reactant Measured value of control Measured value of sample b spiked with Cross-Reactant % Recovery = 100 x Measured Value of Control Interference Potential interference in the ARCHITECT i Valproic Acid assay from the following compounds is designed to have a mean recovery of 100 ± 10% of the control results at the levels indicated. A study based on guidance from the CLSI Protocol EP7-A2 22 was performed for the ARCHITECT i Valproic Acid assay. Serum specimens with valproic acid levels were targeted at 50 and 100 µg/ml and supplemented with the following potentially interfering compounds. The mean percent recovery in this study ranged from 98% to 109%.* Potentially Interfering Compound Triglycerides Hemoglobin Bilirubin Low Protein High Protein 3000 mg/dl 500 mg/dl 20 mg/dl 3 gm/dl 13 gm/dl Evaluation of Other Potentially Interfering Compounds The ARCHITECT i Valproic Acid assay is designed to have a mean recovery of 100 ± 10% in the presence of HAMA and rheumatoid factor (RF). In a study, the ARCHITECT i Valproic Acid assay was evaluated by testing specimens with HAMA and RF to further assess the clinical specificity. Five specimens positive for HAMA and five specimens positive for RF were evaluated for percent recovery with valproic acid spiked into each specimen to target concentrations of 50 and 100 µg/ml. The mean percent recovery for HAMA specimens ranged from 103% to 104% and for RF specimens ranged from 103% to 109%.* Due to the structure of valproic acid (a long chain fatty acid) and the high sensitivity of the assay, some forms of plasticizers, varnishes, paint fumes and fatty acids can interfere with the ARCHITECT i Valproic Acid Reagents yielding questionable results. To avoid interference, do not store any materials listed in the PROCEDURE, Materials Provided or Materials Required but not Provided sections where contact with these materials, or fumes from these materials, can occur. Method Comparison The ARCHITECT i Valproic Acid assay is designed to have a slope of 1.0 ± 0.1 and a correlation coefficient (r) of 0.95 for specimens when compared to AxSYM Valproic Acid. A study was performed using serum specimens and were analyzed using the Passing-Bablok a regression method and are summarized in the following table.* ARCHITECT i Valproic Acid vs. AxSYM Valproic Acid Number of Observations Slope (95%CI b ) Intercept (95%CI) Correlation Coefficient (0.956 to 1.003) ( to 1.684) Specimen Range (ARCHITECT) = 3.13 to µg/ml Specimen Range (AxSYM) = 3.32 to µg/ml a A linear regression method with no special assumptions regarding the distribution of the samples and measurement errors. 23 b Confidence Interval (CI) A bias analysis of ARCHITECT i Valproic Acid vs. AxSYM Valproic Acid was performed on the same 152 specimens in the range of 3.13 to µg/ml and 3.32 to µg/ml respectively. The following representative data are provided to aid in understanding the difference between the two assays. The average bias exhibited by ARCHITECT vs. AxSYM in this study was %. The 95% confidence interval of that average bias is % to 0.410%. Within the typical therapeutic range of valproic acid therapy (50 to 100 µg/ml, as read in the AxSYM), the average bias was % with a 95% confidence interval of % to 0.736%. Results of the study are summarized below.* The vertical lines depict the typical therapeutic range of valproic acid therapy. * Representative data; results in individual laboratories may vary from 6 1P _Eng_ReIn.indd 6 9/3/2009 1:53:49 PM

7 BIBLIOGRAPHY 1. Pinder RM, Brogden RN, Speight TM, et al. Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs 1977;13: Simon D, Penry JK. Sodium di-n-propylacetate (DPA) in the treatment of epilepsy. Epilepsia 1975;16: Bruni J, Wilder BJ. Valproic acid. Review of a new antiepileptic drug. Arch Neurol 1979;36: Browne TR. Valproic acid. N Engl J Med 1980;302(12): Coulter DL, Wu H, Allen RJ. Valproic acid therapy in childhood epilepsy. JAMA 1980;244(8): Sherard ES, Steiman GS, Couri D. Treatment of childhood epilepsy with valproic acid: results of the first 100 patients in a 6-month trial. Neurology 1980;30: Redenbaugh JE, Sato S, Penry JK, et al. Sodium valproate: pharmacokinetics and effectiveness in treating intractable seizures. Neurology 1980;30: Dren AT, Giardina WJ, Hagen NS. Valproic acid. In: Goldberg ME. Pharmacological and Biochemical Properties of Drug Substances. Washington, DC: American Pharmaceutical Association Academy of Pharmaceutical Sciences;1979: US Department of Labor, Occupational Safety and Health Administration, 29 CFR Part , Bloodborne pathogens. 10. US Department of Health and Human Services. Biosafety in Microbiological and Biomedical Laboratories, 5th ed. Washington, DC: US Government Printing Office, January World Health Organization. Laboratory Biosafety Manual. 3rd ed. Geneva: World Health Organization; Clinical and Laboratory Standards Institute. Protection of Laboratory Workers from Occupationally Acquired Infections: Approved Guideline Third Edition. CLSI Document M29-A3. Wayne, PA: Clinical and Laboratory Standards Institute; Guder WG, Narayanan S, Wisser H, Zawta B. Valproate. In: Samples: From the Patient to the Laboratory. 3rd ed. Germany: Wiley-VCH GmbH & Co. KGaA 2003;Annex [CD-ROM]: Schroff RW, Foon KA, Beatty SM, et al. Human anti-murine immunoglobulin responses in patients receiving monoclonal antibody therapy. Cancer Res 1985;45: Primus FJ, Kelley EA, Hansen HJ, et al. Sandwich -type immunoassay of carcinoembryonic antigen in patients receiving murine monoclonal antibodies for diagnosis and therapy. Clin Chem 1988;34(2): Boscato LM, Stuart MC. Heterophilic antibodies: A problem for all immunoassays. Clin Chem 1988;34(1): Lewis JR. Valproic acid (depakene): a new anticonvulsant agent. JAMA 1978;240(20): Adams DJ, Luders H, Pippenger C. Sodium valproate in the treatment of intractable seizure disorders: a clinical and electroencephalographic study. Neurology 1978;28: Garossino A. Valproic acid. Can Pharm J 1979;112: National Committee for Clinical Laboratory Standards. Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline Second Edition. NCCLS document EP5-A2. Wayne, PA: NCCLS, National Committee for Clinical Laboratory Standards. Protocols for Determination of Limits of Detection and Limits of Quantitation; Approved Guideline. NCCLS document EP17-A. Wayne, PA: NCCLS, Clinical and Laboratory Standards Institute. Interference Testing in Clinical Chemistry; Approved Guideline Second Edition. CLSI document EP7-A2. Wayne, PA: Clinical and Laboratory Standards Institute, Passing H, Bablok W. A new biometrical procedure for testing the equality of measurements from two different analytical methods. J Clin Chem Clin Biochem 1983;21(11): RELATED READING Physician s Desk Reference. 62nd ed. Montvale, NJ: Thomson Healthcare Inc ARCHITECT, Chemiflex, and AxSYM are trademarks of Abbott Laboratories in various jurisdictions. All other trademarks are property of their respective owners. ABBOTT Max-Planck Ring Wiesbaden Germany Produced by DENKA SEIKEN CO., LTD. Tokyo, Japan for Abbott Distributed by Abbott Laboratories Abbott Park, IL USA and ABBOTT, Wiesbaden, Germany Product of Japan August , 2009 Abbott Laboratories 7 1P _Eng_ReIn.indd 7 9/3/2009 1:53:50 PM